Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

• the present invention relates to iodonium salt fluoridation. Specifically, the present invention relates to a method for the fluoridation of an iodonium salt wherein the reaction is carried out following storage of a solution of said iodonium salt.
• the invention is also particularly suitable for carrying out radiofluoridation of said iodonium salt.
• the radiofluoridated compound obtained by the method of the invention is useful for inclusion in pharmaceutical compositions, e.g. for use in positron emission tomography (PET) imaging.
• PET positron emission tomography
• the invention relates to a kit for the facile performance of the method of the invention as well as a cassette for the automated performance of the method of the invention.
• Nucleophilic substitution by fluoride is regarded as one of the most attractive ways to introduce fluorine into an organic compound.
• Aromatic nucleophilic substitution using the [ 18 F] fluoride anion to displace a suitable leaving group from an electron deficient aromatic ring is a well-known known method for the production of [ 18 F] fluoroarenes.
• the nucleophilic substitution reaction is illustrated below:
• WG represents between 1 and 4 electron withdrawing groups and LG represents a suitable leaving group, e.g. fluoro, bromo, nitro, tertiary amino or iodo.
• WO 2005/061415 identifies that decomposition of iodonium salts by a free radical chain reaction process is a significant factor in the observed yield variability (reported e.g. by Pike et al J. Chem. Soc. Chem. Comm. 1995: 2215-16) of radiofluoridation reactions using iodonium salts.
• the inclusion of a free radical trap in the reaction mixture was demonstrated in WO 2005/061415 to block the radical chain decomposition pathway for iodonium salts such that the reaction leading to radiofluoridation occurs preferentially and the yield of the desired radiofluorinated product becomes reproducible.
• [ 18 F]-labelled compounds comprising a [ 18 F]-fluoroalkenyl group have also been synthesised using iodonium salt chemistry analogous to that described for obtaining [ 18 F]-fluoroarenes (WO 2007/073200). Inclusion of a free radical trap in the reaction mixture was also reported in this patent application.
• the present invention provides a method for fluoridation of an iodonium salt wherein a solution of the iodonium salt comprising a free radical trap is stored before the reaction is carried out.
• the method of the invention surprisingly results in increased yields of the desired fluorinated product.
• the ability to store the iodonium salt solution conveniently enables provision of a pre-prepared solution for use in the method of the invention.
• the present invention also provides a kit comprising the iodonium salt solution in a suitable container for storage.
• a cassette is also provided which is suitable for carrying out the method of the invention on an automated synthesiser.
• the method of the present invention permits both to be advantageously contained in a single vial.
• the automated method of the invention is particularly convenient when the method of the invention is radiofluoridation.
• the present invention relates to a method for the synthesis of a fluorine-labelled compound, said method comprising:
• fluorine-labelled compound of the method of the invention is a chemical compound whose chemical formula includes at least one fluorine atom, wherein the term “fluorine atom” encompasses both non-radioactive and radioactive isotopes of fluorine.
• the fluorine atom is the radioactive isotope 18 F.
• the fluorine-labelled compound of the method of the invention is of the general formula Q-F, wherein Q is as defined below for Formula I, and F represents the fluorine atom.
• the “iodonium salt solution” of the method of the invention comprises an iodonium salt.
• iodonium salt is defined in the present invention as a compound comprising an ion of the form Y 2 I + .
• the iodonium salt is present in the iodonium salt solution at a concentration of between 0.001-0.1M, preferably 0.01-0.05M, and most preferably 0.01-0.02M. Preferred iodonium salts are described in more detail below.
• the iodonium salt solution also comprises a free radical trap.
• free radical trap is defined herein as any agent that interacts with free radicals and inactivates them.
• a suitable free radical trap in the method of the invention is selected from 4-aminobenzoic acid, 2,6-di-tert-butyl-4-methylphenol (BHT), 1,2-diphenylethylene (DPE), galvinoxyl, gentisic acid, hydroquinone, 2,2,6,6-Tetramethylpiperidine-N-Oxide (TEMPO), thiophenol, ascorbate, para-amino benzoic acid (PABA), ⁇ -carotene and DL- ⁇ -tocopherol.
• BHT 2,6-di-tert-butyl-4-methylphenol
• DPE 1,2-diphenylethylene
• TEMPO 2,2,6,6-Tetramethylpiperidine-N-Oxide
• thiophenol ascorbate
• para-amino benzoic acid PABA
• Preferred free radical traps for use in the method of the invention are TEMPO and DPE, with TEMPO being most preferred.
• the iodonium salt solution usually contains at least 1 mole percent of the free radical trap and preferably about 2-500 mole percent. A more preferred range is from about 10 to 400 mole percent of free radical trap in the solution.
• a suitable “organic solvent” for the iodonium salt solution may be selected from acetonitrile (ACN), dimethylformamide (DMF), dimethylsulphoxide (DMSO), dimethylacetamide (DMAC), tetrahydrofuran (THF), dioxan, 1,2 dimethoxyethane (DME), sulpholane, or N-methylpyrrolidininone.
• Preferred organic solvents herein are ACN, DMF, DMSO, DMAC, and THF, most preferably ACN, DMF, and DMSO.
• the organic solvent is preferably degassed prior to use, a step that is carried out e.g. by bubbling nitrogen or argon through the gas for a period of around a few minutes.
• the organic solvent is “dry”, meaning that the level of water present is 1000 ppm or less, more suitably 600 ppm or less, and preferably 100 ppm or less. This is preferred because reactivity of the fluoride ion with the iodonium salt in the treating step is enhanced when the reaction is carried out with a dry solvent, and it is convenient to carry out the treating step using the stored iodonium salt solution without further manipulation.
• a suitable “storage container” for storage of the iodonium salt solution is one which does not interact with any components of the synthesis reaction, optionally permits maintenance of sterile integrity, plus optionally allows for an inert headspace gas (e.g. nitrogen or argon), whilst also optionally permitting addition and withdrawal of solutions by syringe.
• Such storage containers are preferably liquid-tight or gas-tight jars, flasks, ampoules and vials, the seal being provided by a liquid-tight or gas-tight closure such as a lid, stopper, or septum.
• a most preferred such storage container is a septum-sealed vial, wherein the gas-tight closure is crimped on with an overseal (typically of aluminium).
• Such storage containers have the additional advantage that the closure can withstand vacuum if desired, e.g. to change the headspace gas or degas solutions and can withstand an overpressure, e.g. to aid in the removal of the solution from the container.
• the iodonium salt solution is preferably stored in the dark. More specifically it is preferred that UV light is specifically excluded, because it is believed that free-radical degradation of the iodonium salt in solution is stimulated by UV light.
• the storage container may be made of brown glass, or the storage container may be wrapped with aluminium foil during storage.
• Treatment of the iodonium salt solution with a fluoride ion source may be effected in the presence of either (i) an organic solvent of the type described above for the iodonium salt solution, or (ii) an ionic liquid such as an imidazolium derivative (e.g. 1-ethyl-3-methylimidazolium hexafluorophosphate), a pyridinium derivative (e.g., 1-butyl-4-methylpyridinium tetrafluoroborate), a phosphonium compound, or tetralkylammonium compound.
• an imidazolium derivative e.g. 1-ethyl-3-methylimidazolium hexafluorophosphate
• a pyridinium derivative e.g., 1-butyl-4-methylpyridinium tetrafluoroborate
• a phosphonium compound e.g., 1-butyl-4-methylpyridinium tetraflu
• the treating step of the method of the invention is suitably carried out at a non-extreme temperature, e.g., 15° C. to 180° C., preferably at the higher end of the range, e.g. from 80° C. to 150° C., and particularly at or around 120° C.
• the organic solvent selected for fluoridation is most conveniently the same organic solvent used for storage of the iodonium salt solution. It will be appreciated by the skilled person that some of the temperatures described herein for carrying out the fluoridation reaction exceed the boiling point of the organic solvent.
• the reaction vessel is sealed so that the pressure increases with the rising temperature and consequently raises the boiling point. For example, acetonitrile boils about 80° C. but reactions are possible in a sealed vessel at 120° C. without boiling of acetonitrile.
• reaction vessel for carrying out the fluoridation reaction will depend on the nature and quantity of reactants used. Suitable reaction vessels are made from materials that allow the desired reaction to progress without interference. Such reaction vessels include standard laboratory glassware such as beakers and flasks, as well as cartridges for automated synthesis and microfabricated vessels, all of which are familiar to those of skill in the art.
• step (c) where the reaction solvent comprises water
• the reaction solvent comprises water
• Fluoridation reactions are commonly carried out using anhydrous reaction solvents (Aigbirhio et al J. Fluor. Chem. 1995; 70: 279-87).
• the removal of water from the fluoride ion is referred to as making “naked” fluoride ion and is intended to increase the reactivity of the fluoride ion as well as to avoid hydroxylated by-products resulting from the presence of water (Moughamir et al Tett. Letts. 1998; 39: 7305-6). Therefore, in one embodiment, the solvent used for fluoridation is “dry”, as defined previously herein.
• a further step typically used in the art to improve the reactivity of fluoride ion for fluoridation reactions is to add a cationic counterion prior to the removal of water.
• the counterion should possess sufficient solubility within the anhydrous reaction solvent to maintain the solubility of the fluoride ion. Therefore, counterions that have been used include large but soft metal ions such as rubidium or caesium, potassium complexed with a cryptand such as KryptofixTM, or tetraalkylammonium salts.
• a preferred counterion for fluoridation reactions is potassium complexed with a cryptand such as KryptofixTM because of its good solubility in anhydrous solvents and enhanced fluoride reactivity.
• the “fluoride ion source” of the present invention is suitably selected from potassium fluoride, caesium fluoride and tetraalkylammonium fluoride.
• the preferred fluoride ion source of the invention is potassium fluoride activated with KryptofixTM Most reagents described in this paragraph are available from chemical suppliers such as Sigma Aldrich. Tetraalkylammonium salts can be obtained from ABX Chemicals.
• a preferred iodonium salt of the method of the invention is a compound of Formula I:
• Alkyl used either alone or as part of another group, is defined herein as any straight or branched saturated or unsaturated C n H 2n+1 group, wherein unless otherwise specified n is an integer between 1 and 10.
• Alkyl groups include e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, 1-methylpropyl, pentyl, isopentyl, sec-pentyl, hexyl, heptyl, and octyl.
• cycloalkyl is any cyclic alkyl wherein n of C n H 2n + 1 , unless otherwise specified, is an integer between 3 and 10.
• examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
• Aryl is defined herein as any mono-, bi- or tri-cyclic C 5-14 molecular fragment or group comprising at least one aromatic ring, and preferably having 5 to 6 ring members in each ring.
• Aryl groups include purely aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane, and biphenyl, as well as radicals comprising at least one aromatic ring fused with one or more cycloalkyl or heterocycloalkyl rings.
• heteroalkyl “heterocycloalkyl”, and “heteroaryl” as defined herein are, respectively, an alkyl, a cycloalkyl or an aryl as defined above, wherein at least one atom in the chain is a heteroatom selected from N, S or O.
• Alkoxyalkyl is a C 2-10 straight chain or branched alkyl group with a terminal oxygen linking the alkyl group to the rest of the molecule.
• Alkoxyalkyl includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and so on.
• Carboalkoxy embraces alkoxyalkyl radicals, as defined above, attached to one of two unshared bonds in a carbonyl group, wherein a “carbonyl” group is a functional group composed of a carbon atom double-bonded to an oxygen atom, i.e. C ⁇ O.
• alkenyl refers to an acyclic hydrocarbon radical containing at least one double bond. Such alkenyl radicals contain from 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms and more preferably 2 to 6 carbon atoms. Examples of suitable alkenyl radicals include propenyl, buten-1-yl, isobutenyl, penten-1-yl, 2-2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl, hepten-1-yl, and octen-1-yl.
• alkenylaryl is used herein to refer to a C 7-20 group consisting of an alkenyl group as defined herein linked to an aryl group as defined herein, e.g. phenyl-butenyl, and phenyl-pentenyl.
• An “alkenylheteroaryl” is an alkenylaryl group comprising one or more heteroatoms in the aryl moiety, wherein said heteroatoms are selected from N, S and O.
• alkynyl refers to an acyclic hydrocarbon radical containing one or more triple bonds, such radicals containing from 2 to 10 carbon atoms, preferably having 2 to 8 carbon atoms and more preferably 2 to 6 carbon atoms.
• alkynyl radicals include ethynyl, propynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl.
• alkynylaryl is used herein to refer to a C 7-20 radical consisting of an alkynyl group as defined herein linked to an aryl group as defined herein.
• alkyl means —CO-alkyl wherein alkyl is as defined above.
• “Aroyl” means an —CO-aryl group wherein the aryl group is as defined above.
• Exemplary groups include benzoyl and 1- and 2-naphthoyl.
• “Carbamyl” means the radical —C(O)NH 2 , wherein one or both hydrogens may be substituted with an alkyl or an aryl group, as defined above.
• nitro refers to —NO 2 .
• cyano refers to —CN.
• halo means a halogen substituent selected from fluorine, chlorine, bromine, and iodine, including isotopes thereof.
• haloalkyl haloalkenyl
• haloalkoxy represent alkyl, alkenyl and alkoxy groups, respectively, as defined herein, substituted with one or more halo groups.
• hydrocarbyl refers to a radical which primarily comprises carbon and hydrogen atoms.
• a hydrocarbyl group may for example be alkyl, cycloalkyl, aryl, alkoxyalkyl, carboalkoxy, alkenyl, alkenylaryl, alkenylheteroaryl, alkynyl, acyl, aroyl, or carbamyl, all of which are defined above.
• any protecting groups may be removed by simple procedures which are also standard in the art.
• protecting group is meant a group which inhibits or suppresses undesirable chemical reactions, but which is designed to be sufficiently reactive that it may be cleaved from the functional group in question under mild enough conditions that do not modify the rest of the molecule. After deprotection, the desired in vivo imaging agent is obtained.
• Protecting groups are well known to those skilled in the art and are suitably chosen from, for amine groups: Boc (where Boc is tert-butyloxycarbonyl), Fmoc (where Fmoc is fluorenylmethoxycarbonyl), trifluoroacetyl, allyloxycarbonyl, Dde [i.e. 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl] or Npys (i.e. 3-nitro-2-pyridine sulfenyl); and for carboxyl groups: methyl ester, tert-butyl ester or benzyl ester.
• suitable protecting groups are: methyl, ethyl or tert-butyl; alkoxymethyl or alkoxyethyl; benzyl; acetyl; benzoyl; trityl (Trt) or trialkylsilyl such as tetrabutyldimethylsilyl.
• suitable protecting groups are: trityl and 4-methoxybenzyl. Suitable protection and deprotection methodologies may be found, e.g., in Protecting Groups in Organic Synthesis, Theodora W. Greene and Peter G. M. Wuts, published by John Wiley & Sons Inc (1999).
• R 1 to R 5 are most suitably each hydrogen.
• one of the groups R 1 to R 5 e.g. the group R 3
• a preferred Q group is either a C 5-14 aryl, or a C 4-13 heteroaryl group.
• Most preferred are monocyclic aryl or heteroaryl groups including phenyl, pyridyl, pyrazolyl, bicyclic aryl or heteroaryl groups including naphthalyl, quinolinyl, or tricyclic aryl or heteroaryl groups wherein at least one aryl or heteroaryl group is fused with a cycloalkyl group.
• a preferred heteroatom is N.
• Preferred R 6-8 groups include —C( ⁇ O), hydroxyl, NH 2 , C 1-6 alkyl, —SO 2 —C 1-6 alkyl, C 1-6 cycloalkyl, C 1-6 heteroalkyl, C 1-6 alkoxyalkyl, C 5-14 aryl, and C 4-13 heteroaryl, wherein any heteroatoms are preferably N or O and most preferably N.
• the iodonium salt of the invention may alternatively be solid support-bound, as in Formula Ia:
• alkylene means a linear saturated divalent hydrocarbon moiety of 1-20 carbon atoms or a branched saturated divalent hydrocarbon moiety.
• arylene refers to a C 5-12 aromatic divalent hydrocarbon moiety.
• Alkoxyalkylene is an alkylene group as defined above which further comprises an oxygen atom in the chain, i.e. an ether linkage.
• Haloalkylene is an alkylene group as defined above which is substituted with one or more halo groups, wherein halo is as defined above.
• a suitable solid support X may be selected from polymers such as polystyrene (which may be block grafted, e.g. with polyethylene glycol), polyacrylamide or polypropylene, or glass or silicon coated with such a polymer.
• the solid support may be in the form of small discrete particles such as beads or pins, or as a coating on the inner surface of a cartridge or microfabricated vessel.
• linker L The function of the linker L is to space the reactive site sufficiently far from the solid support structure so as to maximise reactivity.
• linkers and solid supports are well known to those skilled in the art of to solid-phase chemistry, e.g. as described in Florencio Zaragoza Dorwald “Organic Synthesis on Solid Phase: Supports, Linkers, Reactions” Wiley-VCH (2000).
• Examples of the synthesis and fluoridation of a number of solid-phase bound iodonium salts of Formula Ia of the present invention are described in the experimental section of WO 2005/061415.
• an iodonium salt solution for use in a fluoridation reaction would be prepared with the intention to use the solution immediately upon, or very soon after, its preparation (see e.g. Experimental section of Carroll et al 3. Fluorine Chem. 2007; 128: 127-132).
• the present inventors unexpectedly observed that storing the iodonium salt solution prior to treating with a fluoride ion source permitted successful synthesis of the desired fluorine-labelled compound.
• the yields were observed to be, increased following storage in comparison to using the iodonium salt solution as defined herein immediately after preparation. This observation was surprising as the conventional wisdom in the art is that degradation of the components of a solution would be expected to take place during storage, thereby resulting in reduced yields of the desired product.
• the temperature of storage of the iodonium salt solution is suitably above the freezing point of said solution, and less than or equal to 30° C.
• the “freezing point” is the temperature at which the liquid changes state from a liquid to a solid. The temperature remains at this point until all the liquid has solidified. It is invariable under similar conditions of pressure, e.g., the freezing point of water under standard atmospheric pressure is 0° C. In the context of the present invention, the freezing point of a liquid is to be taken as the freezing point under standard atmospheric pressure. It is to be understood that “above the freezing point” is any temperature at or above the minimum temperature at which the liquid is entirely in the liquid state.
• a preferred temperature range for storage of the iodonium salt solution is between 1 and 30° C., most preferably between 1 and 25° C., especially preferably between 1 and 20° C., most especially preferably between 1 and 10° C., and ideally between 1 and 5° C.
• a temperature of between 1 and 5° C. is the typical temperature range for refrigeration and is therefore easily accessible.
• a longer storage period is desirable where the iodonium salt solution is manufactured centrally, and then shipped to customers.
• a preferred storage period is between 12 hours and 3 months, most preferably between 1 day and 1 month, especially preferably between 1-7 days, and most especially preferably between 3-5 days.
• the method of the invention is carried out wherein the fluoride ion source is a [ 18 F]-fluoride ion source.
• the radiochemistry is performed using a nucleophilic radiofluorinating agent such as [ 18 F] caesium fluoride or [ 18 F] potassium fluoride.
• These radiofluorinating agents are prepared from cyclotron-produced no carrier added (NCA) [ 18 F] fluoride (as described by Aigbirhio et al J Fluorine Chem 1995; 70: 279).
• [ 18 F]-fluoride ion is typically obtained as an aqueous solution which is a product of the irradiation of an [ 18 O]-water target.
• Conventional practice is to carry out various steps to convert [ 18 F]-fluoride into a reactive nucleophilic reagent, such that it is suitable for use in nucleophilic radiolabelling reactions. As with non-radioactive fluoridations, and as discussed earlier, these steps include the elimination of water from [ 18 F]-fluoride ion and the provision of a suitable counterion (“Handbook of Radiopharmaceuticals” 2003; Welch & Redvanly eds.; ch. 6: 195-227). Nucleophilic radiofluorination reactions are then carried out using anhydrous solvents (Aigbirhio et al J. Fluor. Chem. 1995; 70: 279-87).
• the [ 18 F]-labelled compound is an [ 18 F]-labelled radiotracer, i.e. an [ 18 F]-labelled compound that following administration binds to a particular biological target within a subject, and is detectable using positron emission tomography (PET) imaging.
• PET positron emission tomography
• the [ 18 F]-labelled-radiotracer is comprised in a pharmaceutical composition.
• a “pharmaceutical composition” is defined in the present invention as a formulation comprising the [ 18 F]-labelled-radiotracer of the invention or a salt thereof in a form suitable for administration to humans.
• the pharmaceutical composition may be administered parenterally, i.e. by injection, and is most preferably an aqueous solution.
• the method of the invention is a radiofluoridation method, particularly for the production of an [ 18 F]-labelled radiotracer, it may further comprise one or more of the following steps in any order:
• the iodonium salt solution of the method of the invention can be provided as part of a kit suitable for carrying out the method of the invention.
• Said kit forms a further aspect of the present invention and comprises the iodonium salt solution in a storage container, as defined above for the method of the invention.
• a kit is particularly convenient when the fluorine-labelled compound is a 18 F-labelled compound such as a [ 18 F]-labelled-radiotracer, wherein said kit is suitable for preparation of said 18 F-labelled compound at a radiopharmacy, PET centre, or nuclear medicine department.
• the kit may contain a cartridge which can be plugged into a suitably adapted automated synthesiser, described in more detail below.
• kits are disposable to minimise the possibilities of contamination between runs and to ensure sterility and quality assurance.
• the fluoridation method of the invention can be automated, and this is a preferred embodiment of the method of the invention, particularly for radiofluoridation.
• [ 18 F]-radiotracers are now often conveniently prepared on an automated radiosynthesis apparatus.
• Such apparatus commonly comprises a “cassette”, often disposable, in which the radiochemistry is performed, which is fitted to the apparatus in order to perform a radiosynthesis.
• the cassette normally includes fluid pathways, a reaction vessel, and ports for receiving reagent vials as well as any solid-phase extraction cartridges used in post-radiosynthetic clean up steps.
• the iodonium salt solution in its storage container as described herein may be housed in such a disposable or removable cassette designed for use with an automated synthesis apparatus. Therefore, in another aspect, the present invention further provides a cassette for an automated synthesis apparatus comprising the iodonium salt solution in a storage container as described hereinbefore.
• the cassette can be provided complete with all of the reagents required for the fluoridation reaction, except for the radiofluoride.
• the iodonium salt is provided in solution in a single vial of the cassette, wherein said vial is a storage container as described herein.
• a cassette for use in an automated apparatus based on currently-known methods for fluoridation of iodonium salts would require one vial for the solid iodonium salt, and another vial for the organic solvent. Therefore, the method of the present invention means that the associated cassette for automated synthesis requires fewer components than would be necessary to automate any presently-known method. Furthermore, the length of time taken to complete the automated synthesis is shortened as there is no step of dissolving the iodonium salt.
• the present invention will also be understood to encompass use of the kit of the invention, or of the cassette of the invention for carrying out the method of the invention.
• the suitable and various preferred embodiments of the features of the kit, cassette and method of the invention are as previously described.
• Examples 1 and 2 describe fluoridation of a quinoyliodonium salt following storage of said quinoyliodonium salt for 3 and 5 days, respectively.
• RCP radiochemical purity, defined as the amount of desired radioactive product as a percentage of all radioactivity.
• RCY radiochemical yield, defined as the RCP multiplied by the decay-corrected percentage of radioactivity recovered from the reaction vessel.
• Chlorine gas was generated by drop-wise addition of concentrated hydrochloric acid on to potassium permanganate. The gas evolved was bubbled through water to remove any HCl gas, then through the reaction mixture then twice through 20% sodium hydroxide solution to destroy any unreacted chlorine.
• a chlorine gas detector was used throughout the experiment and was set to alarm at 0.10 ppm. The exhaust and joints were monitored for trace amounts of chlorine using wet starch paper.
• 3-Iodopyridine dichloride (1.66 g, 5 mmol) was added to 10M aqueous sodium hydroxide (10 mL) solution with stirring and the suspension was stirred for 0.5 h when the solid was collected by filtration and washed with water (5 mL) and air dried for 0.5 h. The colourless solid was then added to acetic acid (5 mL) and stirred at room temperature for 0.5 h when water (30 mL) was added and the mixture was extracted with dichloromethane (2 ⁇ 50 mL), dried (MgSO 4 ) and concentrated in vacuo to give a yellow oil.
• Trifluoroacetic acid (0.15 mL, 2 mmol) was added dropwise to a stirred solution of 3-iodopyridine diacetate (0.23 g, 1 mmol) in dichloromethane at ⁇ 40° C. and stirred for 0.5 h when the solution was allowed to warm to room temperature for 1 h after which time it was re-cooled to ⁇ 40° C. and anisole (0.11 mL, 1 mmol) added dropwise and the reaction mixture allowed to warm to room temperature overnight. The reaction mixture was concentrated in vacuo to give a light brown oil. Crystallisation gave the title compound as a colourless crystalline solid (0.22 g, 0.52 mmol, 52%); mp 150-151° C.
• [ 18 F] fluoride (typically 100-150 MBq) was transferred to the reaction vessel from a P6 vial by suction.
• the solution was then dried by heating at 100° C. under a flow of nitrogen gas (0.3 L/Min) for 15 min, during which time acetonitrile aliquots (0.5 mL) were added after 5 and 7 min.
• the vessel was then cooled to 30° C.
• [ 18 F] fluoride was transferred to the reaction vessel from a P6 vial by suction.
• a solution of Kryptofix® 222 (2.5 mg, 6.6 ⁇ 10 ⁇ 6 mols), 0.1M aqueous potassium carbonate (50 ⁇ L, 5 ⁇ 10 ⁇ 6 mols) in acetonitrile (0.5 mL) was added to the P6 vial and the solution transferred to the vessel.
• the solution was then dried by heating at 100° C. under a flow of nitrogen gas (0.3 L/Min) for 15 min.
• the vessel was then cooled to 30° C.
• the RCP was measured by radio-HPLC.
• the RCY is expressed as decay-corrected and is calculated from the RCP and measured activity in the reaction vessel once the reaction is complete.
• [ 18 F] fluoride was transferred to the reaction vessel from a P6 vial by suction.
• a solution of Kryptofix® 222 (2.5 mg, 6.6 ⁇ 10 ⁇ 6 mols), 0.1M aqueous potassium carbonate (50 ⁇ L, 5 ⁇ 10 ⁇ 6 mols) in acetonitrile (0.5 mL) was added to the P6 vial and the solution transferred to the vessel.
• the solution was then dried by heating at 100° C. under a flow of nitrogen gas (0.3 L/Min) for 15 min.
• the vessel was then cooled to 30° C.
• the RCP was measured by radio-HPLC.
• the RCY is expressed as decay-corrected and is calculated from the RCP and measured activity in the reaction vessel once the reaction is complete.

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